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There are few effective treatment options for patients with recurrent or metastatic head-and-neck squamous cell carcinoma. Pembrolizumab showed antitumour activity and manageable toxicity in early-phase trials. We aimed to compare the efficacy and safety of pembrolizumab versus standard-of-care therapy for the treatment of head-and-neck squamous cell carcinoma. We did a randomised, open-label, phase 3 study at 97 medical centres in 20 countries. Patients with head-and-neck squamous cell carcinoma that progressed during or after platinum-containing treatment for recurrent or metastatic disease (or both), or whose disease recurred or progressed within 3–6 months of previous multimodal therapy containing platinum for locally advanced disease, were randomly assigned (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive pembrolizumab 200 mg every 3 weeks intravenously or investigator's choice of standard doses of methotrexate, docetaxel, or cetuximab intravenously (standard-of-care group). The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT02252042, and is no longer enrolling patients. Between Dec 24, 2014, and May 13, 2016, 247 patients were randomly allocated to pembrolizumab and 248 were randomly allocated to standard of care. As of May 15, 2017, 181 (73%) of 247 patients in the pembrolizumab group and 207 (83%) of 248 patients in the standard-of-care group had died. Median overall survival in the intention-to-treat population was 8·4 months (95% CI 6·4–9·4) with pembrolizumab and 6·9 months (5·9–8·0) with standard of care (hazard ratio 0·80, 0·65–0·98; nominal p=0·0161). Fewer patients treated with pembrolizumab than with standard of care had grade 3 or worse treatment-related adverse events (33 [13%] of 246 vs 85 [36%] of 234). The most common treatment-related adverse event was hypothyroidism with pembrolizumab (in 33 [13%] patients) and fatigue with standard of care (in 43 [18%]). Treatment-related death occurred in four patients treated with pembrolizumab (unspecified cause, large intestine perforation, malignant neoplasm progression, and Stevens-Johnson syndrome) and two patients treated with standard of care (malignant neoplasm progression and pneumonia). The clinically meaningful prolongation of overall survival and favourable safety profile of pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma support the further evaluation of pembrolizumab as a monotherapy and as part of combination therapy in earlier stages of disease. Merck Sharp & Dohme, a subsidiary of Merck & Co.

The observation of photocatalytic water splitting on the surface of anatase TiO2 crystals has stimulated many investigations of the underlying processes. Nevertheless, a molecular level understanding of the reaction is not available. Therefore, the work carried out here is focused on improving the understanding of the water splitting mechanism by studying anatase TiO2 surfaces with hybrid-exchange density functional theory calculations. Initially, a simple and systematic methodology for the simulation of constant current scanning tunnelling microscopy (STM) images is developed in order to study TiO2 surfaces. The methodology has to overcome a significant limitation of local basis set calculations: the poor description of the charge density in the vacuum region above the surface. The methodology is tested on various surfaces and the simulated STM images are found to accurately reproduce experimental data. The next step was to re-establish the atomistic structures of the (101), (001) and (100) surfaces. The relative stability of these surfaces is interpreted in terms of the coordination of the surface ions and the geometry surrounding them. Furthermore, the electronic properties are studied. Based on relative positions of the conduction and valence bands of the low-index surfaces studied the (101) and (001) surfaces were identified as the most likely destinations for photo-generated electrons and holes, respectively. The atomistic structure of two surfaces vicinal to the (101) surface - the (514) and (516) surfaces - was established. The surface formation energy of these surfaces is low and the (516) surface contributes significantly (27%) to the surface area of an equilibrium crystallite, which could suggest that this surface is exposed in nanoparticles. The conduction band edge of this surface was computed to be more negative than that of the (101) surface. Thus, if the (516) surface is exposed in nanostructures, it would replace the (101) surface as the most likely destination for photo-generated electrons. Under-coordinated ions at the steps of these vicinal surfaces were identified as preferential adsorption sites and water adsorption was studied at these sites. In general, it was found that water preferentially adsorbs in the molecular adsorption mode on all sites tested, with the exception of the Ti4c on the (514) surface, where the dissociative mode is preferred. Nevertheless, at the (516) step the binding energy of the dissociative adsorption mode is comparable to that of the molecular case. Therefore, if it were possible to preferentially expose the Ti5c-O2c-Ti5c motif from the (516) surface, or even the Ti4c of the (514) surface the reactivity for water photolysis could be enhanced.

Entre os exemplares que constituem acervo do Museu da Ciência da Universidade de Coimbra, insere-se um esqueleto de baleia-comum. No entanto, este exemplar necessita de divulgação e esclarecimento de conteúdo científico. O esqueleto apresenta a falta de alguns ossos (alguns apenas partes, outros na sua totalidade), apresenta o posicionamento incorreto de alguns ossos e apresenta escassez na quantidade de informações disponíveis sobre si. O mesmo esqueleto também se encontra num espaço onde a quantidade de área de circulação disponível ao seu redor não permite que os visitantes tenham grande manobra de circulação e não permite que os visitantes tenham uma visão periférica larga o suficiente para captar todo o exemplar de uma só vez.Esta dissertação apresenta um conceito que atende às necessidades e, ao mesmo tempo, enquadra-se no contexto do Museu da Ciência da Universidade de Coimbra. Esse conceito consiste numa animação digital que apresenta uma série de características morfológicas e fisiológicas relativas à espécie baleia-comum, assim como relata a história da incorporação do exemplar de esqueleto no Museu da Ciência da Universidade de Coimbra. A mesma animação poderá ser acedida fora o espaço físico do museu ou dentro do espaço físico do museu. Fora do espaço físico do museu poderá ser acedida através do acesso ao website do museu, ao introduzir-se o endereço do website num dispositivo compatível. Dentro do espaço físico do museu, poderá ser acedida através do acesso ao websitedo museu ao introduzir-se o endereço do website do museu num dispositivo compatível, ou ao captar-se um código QR com o endereço do website do museu através de um dispositivo compatível.

A Baixa Pombalina que hoje conhecemos resulta da grande reconstrução da cidade de Lisboa que sucedeu o grande terramoto de 1 de Novembro de 1755. O violento abalo, com várias réplicas, ao qual se seguiu um incêndio, que durou vários dias, e um maremoto, teve proporções avassaladoras arrasando cerca de dois terços dos edifícios existentes.Como resposta a esta catástrofe surgiu o sistema construtivo Pombalino, principalmente caracterizado pela utilização em larga escala de um sistema tridimensional contraventado em madeira, conhecido por “gaiola Pombalina”.Apesar da sua excelente qualidade estrutural, os edifícios originais pombalinos têm sido, ao longo dos tempos, alvo de modificações lesivas para a sua estrutura.Este trabalho surge com o intuito de criar um documento que ajude a compreender o funcionamento dos edifícios Pombalinos de modo a não repetir erros estruturalmente lesivos para este tipo de edifícios no futuro.De modo a atingir os objectivos propostos é feita uma descrição do sistema construtivo Pombalino, das principais acções históricas, políticas e legais que o antecederam e das principais alterações estruturais que este tipo de edifícios tem sido alvo ao longo da sua vida.O conhecimento de todos estes aspectos é fundamental para avaliar e assegurar a segurança dos utilizadores deste tipo de edifícios assim como para permitir que este património, de valor inestimável, chegue a futuras gerações em condições de segurança e sustentabilidade face à ocorrência de futuros sismos.

Active packaging is becoming progressively more significant as a response to the dynamic changes in current consumer demand and market tendencies. Active packaging is projected to interact directly with the packaged food or with the headspace within the package with the aim of maintaining or extending product quality and shelf-life. Aiming for sustainability, the potential application as biodegradable films of whey protein concentrate (WPC) was evaluated. Aromatic plant’s extracts present high antioxidant properties, representing an alternative for synthetic food additives. The main objective of this study was to verify the effectiveness of an edible WPC film incorporated with a plant-based extract on retarding the lipid oxidation of fresh salmon. Green tea extract (GTE) was chosen to be incorporated into the active film. Fresh salmon was packaged with the control film (WPC) and with active film (WPC–GTE). The oxidation level of non-packaged samples and packaged samples were tested for different storage times. Four methods were applied to evaluate lipid oxidation state of fresh salmon: peroxide value, p-anisidine value, thiobarbituric acid reactive substances (TBARS) assay, and monitoring of hexanal. The results obtained in this study indicate that the whey protein active film was successfully produced, and it was effective in delaying lipid oxidation of fresh salmon samples until the 14th day of storage.

While chemotherapy treatment can be lifesaving, it also has adverse effects that negatively impact the quality of life. To investigate the effects of doxorubicin chemotherapy on body weight loss, strength and muscle mass loss, and physical function impairments, all key markers of cachexia, sarcopenia, and frailty. Seventeen C57/BL/6 mice were allocated into groups. 1) Control (n = 7): mice were exposed to intraperitoneal (i.p.) injections of saline solution. 2) Dox (n = 10): mice were exposed to doxorubicin chemotherapy cycles (total dose of 18 mg/kg divided over 15 days). The body weight loss and decreased food intake were monitored to assess cachexia. To assess sarcopenia, we measured muscle strength loss using a traction method and evaluated muscle atrophy through histology of the gastrocnemius muscle. To evaluate physical function impairments and assess frailty, we employed the open field test to measure exploratory capacity. Doxorubicin administration led to the development of cachexia, as evidenced by a significant body weight loss (13%) and a substantial decrease in food intake (34%) over a 15-day period. Furthermore, 90% of the mice treated with doxorubicin exhibited sarcopenia, characterized by a 20% reduction in traction strength (p<0,05), a 10% decrease in muscle mass, and a 33% reduction in locomotor activity. Importantly, all mice subjected to doxorubicin treatment were considered frail based on the evaluation of their overall condition and functional impairments. The proposed model holds significant characteristics of human chemotherapy treatment and can be useful to understand the intricate relationship between chemotherapy, cachexia, sarcopenia, and frailty.

Given the need to understand the virulence profile of Proteus mirabilis isolates from cellulitis in broiler chickens and their ability to cause lesions, the present study aimed to characterize genotypically and phenotypically the virulence profiles of two strains of P. mirabilis isolated from cellulitis in broilers, as well as to evaluate their ability to experimentally reproduce the lesions in vivo. The strain with the highest virulence potential (LBUEL-A33) possessed mrpA, pmfA, ucaA, atfA (fimbriae), zapA, ptA (proteases), hpmA (hemolysin), and ireA (siderophore) genes, formed a very strong biofilm, and expressed the pattern of aggregative adhesion and cytotoxicity in Vero cells. The strain with the lowest virulence potential (LBUEL-A34) did not present the pmfA and ucaA genes, but expressed the pattern of aggregative adhesion, formed a strong biofilm, and did not show cytotoxicity. Both strains developed cellulitis in an animal model within 24 h post-inoculation (PI), and the degree of lesions was not significantly altered up to 120 h PI. The LBUEL-A33 strain was also inoculated in combination with an avian pathogenic Escherichia coli (APEC 046), and the lesions showed no significant changes from the individual inoculation of these two strains. Histological analysis showed that the LBUEL-A33 strain developed characteristic cellulitis lesions. Thus, both strains of P. mirabilis isolated in our study have several virulence factors and the ability to develop cellulitis in broilers.

Sézary syndrome (SS) is a rare and aggressive type of cutaneous T-cell lymphoma, with an abnormal inflammatory response in affected skin. The cytokines IL-1B and IL-18, as key signaling molecules in the immune system, are produced in an inactive form and cleave to the active form by inflammasomes. In this study, we assessed the skin, serum, peripheral mononuclear blood cell (PBMC) and lymph-node samples of SS patients and control groups (healthy donors (HDs) and idiopathic erythroderma (IE) nodes) to investigate the inflammatory markers IL-1B and IL-18 at the protein and transcript expression levels, as potential markers of inflammasome activation. Our findings showed increased IL-1B and decreased IL-18 protein expression in the epidermis of SS patients; however, in the dermis layer, we detected increased IL-18 protein expression. In the lymph nodes of SS patients at advanced stages of the disease (N2/N3), we also detected an enhancement of IL-18 and a downregulation of IL-1B at the protein level. Moreover, the transcriptomic analysis of the SS and IE nodes confirmed the decreased expression of IL1B and NLRP3, whereas the pathway analysis indicated a further downregulation of IL1B-associated genes. Overall, the present findings showed compartmentalized expressions of IL-1B and IL-18 and provided the first evidence of their imbalance in patients with Sézary syndrome.

PurposeThe most frequent histology of bladder tumors is urothelial carcinoma. Most are pure urothelial carcinomas (PUC) but up to one-third of the cases present variant histological (VH) features. The aim of this study was to evaluate the role of variant histology in neoadjuvant chemotherapy (NAC) response in patients with urothelial muscle-invasive bladder cancer.MethodsWe retrospectively analyzed data from 77 patients with bladder cancer who performed neoadjuvant chemotherapy at two institutions.ResultsComplete pathological response (ypT0) was higher in patients with PUC (38.5%), comparing with VH (12%). Logistic regression analysis demonstrated that variant histology is associated with an 89% lesser likelihood of tumor downstaging, with advanced clinical T stages and positive smoking history as independent predictors. The estimated mean cancer-specific survival was 68.91 months for PUC patients and 50.23 months for VH patients (log rank test, P = 0.024). Multivariate Cox regression analysis demonstrated that VH and clinical T stage were independent predictors of cancer-specific survival, indicating a worse outcome for patients with VH and advanced clinical T stages.ConclusionsThere are only a few retrospective studies evaluating the clinical impact of variant histology tumors, which are mainly managed as PUC. Our results demonstrate that VH is associated with a worse likelihood of tumor downstaging after NAC and a worse cancer-specific survival in bladder cancer patients. There is a need for further studies and genetic analysis to identify the patients most likely to achieve ypT0 status and downstaging after NAC.